Sorbs2 targeting and BK channel regulation in the coronary artery of patients with type 1 diabetes

1 型糖尿病患者冠状动脉中的 Sorbs2 靶向和 BK 通道调节

• 批准号: 10677743
• 负责人: Tong Lu
• 金额: $ 68.84万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677743
• 关键词: Animals; Atherosclerosis; Binding; Biological Assay; Biophysics; Biotinylation; Blood Glucose; Blood Vessels; Blood flow; Body Weight; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinic; Clinical; Coronary; Coronary Circulation; Coronary artery; Coronary heart disease; Cytoskeletal Proteins; Diabetes Mellitus; Diabetic Nephropathy; Down-Regulation; Event; Exhibits; FDA approved; Functional disorder; Human; Impairment; In Situ; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Knowledge; Ligation; Mediating; Membrane; Membrane Proteins; Molecular; Myocardial Ischemia; Myocardial perfusion; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Pathology; Patients; Physiology; Play; Proteins; Rattus; Regulation; Reporting; Research Personnel; Resolution; Risk; Risk Factors; Role; SH3 Domains; Scaffolding Protein; Schedule; Signal Transduction; Site-Directed Mutagenesis; Smooth Muscle; Smooth Muscle Myocytes; Sulforaphane; Surface; Techniques; Technology; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Video Microscopy; arteriole; diabetic; diabetic patient; endothelial dysfunction; heart function; human tissue; improved; insight; large-conductance calcium-activated potassium channels; molecular targeted therapies; non-diabetic; novel; novel strategies; novel therapeutic intervention; nuclear factor-erythroid 2; patch clamp; pharmacologic; preservation; protein expression; sorbin; treatment strategy; type I and type II diabetes; ultra high resolution; vascular inflammation

Project Summary Type 1 diabetes (T1D) is strongly associated with coronary heart disease. However, the molecular mechanism underlying coronary vascular pathology, especially coronary arterial smooth muscle pathology in human with T1D is incomplete. Vascular BK channels, composed of four pore-forming subunits (BK-α) and four regulatory subunits (BK-β1), are densely expressed in coronary artery smooth muscle cells (SMCs) and are a key determinant of coronary blood flow and cardiac function. Over the last 10 years, we and other investigators have demonstrated that coronary BK channel function is impaired in T1D animals due to increased oxidative stress and it contributes to a worse outcome in myocardial ischemia. However, most of our knowledge of coronary BK channel dysregulation in T1D is obtained from animals and most of studies are focused on the BK-β1 dysregulation in diabetes. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a component of cytoskeleton proteins in vascular SMCs. Sorbs2 is abundantly expressed in cardiovascular tissues and is a downstream target of Nrf2. However, the role of Sorbs2 in vascular pathophysiology is unknown. We have exciting preliminary results showing that Sorbs2 interacts with BK-α and BK-β1 protein and regulates BK channel expression in coronary SMCs. Interestingly, Sorbs2 knockout mice share many common features of coronary BK channelopathy with diabetes, despite being normoglycemic and not obese, indicating that Sorbs2 deficiency is an independent risk of vascular BK channelopathy. Importantly, Sorbs2 expression is significantly reduced in coronary arteries of patients with T1D. Unlike T2D patients, the expression of BK-α, but that of BK- β1, is markedly reduced in the coronary SMCs of patients with T1D. However, the role of Sorbs2 on coronary BK channelopathy and vasculopathy of human T1D has not been established, and the underlying mechanisms regarding the downregulation of BK-α expression in coronary SMCs of T1D patients is unclear. In this project, we will take advantage of the availability of human coronary arteries from T1D patients who are scheduled for cardiac surgery at Mayo Clinic in Rochester (MN) to test our hypothesis that downregulation of Sorbs2 expression contributes to BK channel and vascular dysfunction in the coronary arteries of T1D patients and increase of Sorbs2 expression by pharmacological Nrf2 activation protects coronary BK channel function and vasoreactivity in human tissues with T1D. Results from this study will provide novel insights into the molecular mechanisms underlying BK channelopathy and coronary vasculopathy in T1D and may help develop new strategies for the treatment of cardiovascular complications in T1D patients.

项目摘要 1型糖尿病（T1D）与冠状动脉疾病密切相关。但是，分子机制 潜在的冠状动脉血管病理学，尤其是人类的冠状动脉平滑肌病理学 T1D不完整。血管BK通道，由四个形成孔的亚基（BK-α）和四个调节 亚基（BK-β1）在冠状动脉平滑肌细胞（SMC）中不表达，是钥匙 冠状动脉血流和心脏功能的决定因素。在过去的十年中，我们和其他调查人员 已经证明，由于氧化增加，T1D动物中冠状动脉BK通道功能受损 压力和心肌缺血的结果更糟。但是，我们的大多数了解 T1D中的冠状动脉BK通道失调是从动物中获得的，大多数研究都集中在 糖尿病中的BK-β1失调。 Sorbin和SH3结构域的蛋白2（Sorbs2）是 血管SMC中的细胞骨架蛋白。 Sorbs2在心血管组织中绝对表达，是 NRF2的下游目标。但是，Sorbs2在血管病理生理学中的作用尚不清楚。我们有 令人兴奋的初步结果表明SORBS2与BK-α和BK-β1蛋白相互作用并调节BK 冠状动脉SMC中的通道表达。有趣的是，Sorbs2淘汰小鼠有许多常见的特征 患有糖尿病的冠状动脉BK通道病，多皮是正常的，不是肥胖的，表明Sorbs2 缺乏是血管BK通道病的独立风险。重要的是，sorbs2表达显着 T1D患者的冠状动脉动脉降低。与T2D患者不同，BK-α的表达，但BK-的表达 β1在T1D患者的冠状动脉SMC中明显降低。但是，Sorbs2在冠状动脉上的作用 尚未建立人类T1D的BK通道病和血管病，并且是基本的机制 考虑到T1D患者的冠状动脉SMC中BK-α表达的下调尚不清楚。在这个项目中， 我们将利用预定的T1D患者的人类冠状动脉的可用性 罗切斯特梅奥诊所（MN）的心脏手术，以检验我们的假设，即Sorbs2的下调2 表达有助于T1D患者的冠状动脉中的BK通道和血管功能障碍 通过药物NRF2激活增加SORBS2表达的表达可保护冠状动脉BK通道功能和 具有T1D的人体组织中的血管反应性。这项研究的结果将为分子提供新的见解 T1D中BK通道病和冠状动脉血管病的基础机制，可能有助于开发新的 治疗T1D患者心血管并发症的策略。

项目成果

Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis.

• DOI: 10.3389/fimmu.2022.948479
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Zhao-Fleming, Hannah H.;Zahid, Anza;Lu, Tong;Sun, Xiaojing;Pittock, Sean J.;Lee, Hon-Chi;Dubey, Divyanshu
• 通讯作者: Dubey, Divyanshu